The grant will continue development of a major research program devoted to fundamental studies of synthetic chernstry of recently discovered, biologically potent natural substances. The proposed investigations, toward a number of important target molecules, are outlined below. A. Spiroketals- We have described the remaining studies which will finalize our objectives in this area; including completion of breynolide, a significant new lead demonstrating in vivo hypocholesterolemic activity in mammals; and milbemycin alpha1, a potent member of a novel group of macrocyclic lactones with high pesticidal and anthelminthic action. B. Marine Natural Products- We have illustrated plans which will afford access to the terpenoid, dollabellanes, many of which demonstrate powerful antileukemic and antimicrobial activities. These studies have led to synthetic strategies toward the tricyclic 5-8-5 ophiobolane-fusicoccane family, as represented by anadensin, which are important modifiers of plant cell growth and development. Finally, we have outlined explorations of fundamental heterocyclic oxazole chemistry as a precursor to our plans for total synthesis of the ulapualides, extraordinarily potent and unique antitumor marine natural products.